Although there is no shortage of potential drug targets, there are only a handful known low molecular weight
inhibitors of protein-protein interactions (PPIs). One problem is that current efforts are dominated by
low-yield high-throughput screening, whose rigid framework is not suitable for the diverse chemotypes
present in PPIs. Here, we developed a novel pharmacophore-based interactive screening technology that builds
on the role anchor residues, or deeply buried hot spots, have in PPIs, and redesigns these entry points with
anchor-biased virtual multicomponent reactions, delivering tens of millions of readily synthesizable novel
compounds. Application of this approach to the MDM2 /p53 cancer target led to high hit rates, resulting in a
large and diverse set of confirmed inhibitors. Our unique open-access technology promises to both expand
chemical space and develop new probes to study protein function by leveraging in-house small-scale assays
and user-friendly chemistry to rationally design ligands for PPIs with known structure.